Hyperacidity is an entity which is present in various digestive tract pathologic states. In each case it appears with proper intensity, duration and characteristics. It is present in the case of gastric ulcer, gastroesophagic reflux, erosive esophagitis, pathologic hypersecretion such as Zollinger-Ellison syndrome, duodenal erosions or gastric ulcers associated with the administration of non-steroidal anti-inflammatory drugs, infection due to Helicobacter pylori, ulcer due to stress (Dollery, Colin et al.; Therapeutic Drugs Vol. 2; Edic. Churchill Livingstone, UK, 1991), which is incorporated by reference herein in its entirety), consumption of substances harmful to the digestive apparatus (for example, coffee, alcohol, and the like).
The hyperacidity caused by the abnormal or excessive production of acid results in inflammation of the stomach or gastritis. It also results in esophagic involvement when it produces reflux from the stomach to the esophagus.
Numerous drugs have shown to be effective for controlling or suppress hyperacidity as a symptom.
Such drugs have particular characteristics regarding behavior, efficiency and duration of action.
Thus, for example:
1. Anti-acids:
Are generally inorganic soluble or little soluble salts, alone or in combination. Among them are: calcium and magnesium carbonate, sodium bicarbonate, aluminum hydroxide, aluminum phosphate, and the like.
After their entering into the stomach they neutralize immediately gastric acidity. They act in situ and do not require prior absorption.
They have an immediate therapeutic effect though they are short acting.
2. Alginic acid and its sodium and magnesium salts:
The alginic acid and its salts associates with sodium and potassium bicarbonate have shown that, after entering the stomach environment they form a viscous suspension (or a gel) exerting protecting activity over gastric mucosa. The scientific and patent literature on its activity is wide. Thus, for example:    Mandel K. G.; Daggy B. P.; Brodie D. A; Jacoby, H. L., 2000. Review article: Alginate-raft formulations in the treatment of heartburn and acid reflux. Aliment. Pharmacol. Ther. 14 669-690, which is incorporated by reference herein in its entirety;    Bioadhesive oesophageal bandages: protection against acid and pepsin injury. Man Tang, Peter Dettmar, Hannah Batchelor—International Journal of Pharmaceutics 292 (2005)—169-177, which is incorporated by reference herein in its entirety.
The number of commercially available alginate products for therapeutic use worldwide is also important. Thus, for example, in MIMS (Monthly Index of Medical Specialities) of Great Britain there are mentioned some pharmaceutical products containing sodium alginate and potassium bicarbonate (Gaviscon Advance) for heat, esophagic reflux and dyspepsia, Liquid Gaviscon containing sodium alginate, sodium bicarbonate and calcium carbonate. There is also a composition formed by sodium and magnesium alginate (Gaviscon Infant).
3. Antagonists of H2 histamine receptors:
They reduce the production of histamine which stimulates the formation of acid in the stomach due to the selective blockade of H2 receptors.
Compared with prior art anti-acids, they have longer effect and duration of action (6 to 12 hours) (Goodman y Gilman. Las bases farmacológicas de la terapéutica; Vol I, pág. 1025, X Edición, Mc. Graw Hill, 2003), which is incorporated herein by reference in its entirety.
Preferred examples are: cimetidine, nizatidine, famotidine and ranitidine.
4. Inhibitors of proton pump:
This is the most modern pharmacologic group for this kind of therapeutics. They act by selectively and specifically blocking the H+-K+−-ATPase enzyme of stomach parietal cell. They cause a marked reduction of the production of acid by the stomach parietal cells.
Thus, for example, in patients with duodenal ulcer, oral administration of 20 mg of omeprazole keeps the gastric pH in 3 or greater than 3 for 17 hours. The maximum effect is reached within 4 days of treatment.
Preferred examples are: omeprazole, lansoprazole, esomeprazole, pantoprazole, rabeprazole and the like.
The use of each one of the above mentioned alternatives is associated with the specific characteristic and intensity of the disease state causing hyperacidity.
Anti-acids and alginates have shown immediate effect as they act in the stomach and do not require prior absorption. The control of hyperacidity is rapid but with short duration.
On the other hand, the inhibitors of proton pump do not have immediate effect. Their effect is long because they necessarily have to be absorbed in order to exert their activity. Thus, for example, the absorption of omeprazole is done in the small intestine and is completed by 3-6 hours. Such a behavior causes some technical inconveniencies for the design of a pharmaceutical composition. Since:
a) Omeprazole requires, in fasting state, at least 20 to 30 minutes to reach the intestine.
b) It also requires an additional time for its intestinal absorption.
c) Since it is a scarcely stable substance in acid medium, while it is in the gastric environment, it is easily destructed before it reaches the intestine and, therefore, it should necessarily be protected from said gastric acidity.
The low stability of omeprazole in an acid medium has been widely documented from 1985 (Pilbrant and Cederberg—SCAND. J GASTROENTEROLOGY (1985), 20 (Suppl. 108)—p. 113-120) (Lindberg Per et al.—J MED. CHEM (1986), 29—p. 1327-1329), which is incorporated by reference herein in its entirety. Its half life in water and at a pH of 4 is lower than 10 minutes, being it of about 14 hours at a pH near 7.
Numerous alternatives have been explored to elaborate stable pharmaceutical forms mainly to solve the 2 most important problems (pH and moisture) affecting the stability of omeprazole. Thus, for example:
Britain patent GB No 2,189,698 (1987) describes the elaboration of an oral form of omeprazole characterized for having a core formed by the active principle (omeprazole) with a basic reactant and said core is coated by one or more protecting layers, which are water soluble, and an outer layer of enteric coating, which is incorporated herein by reference in its entirety. The proceeding and the obtained products showed an appropriate resistance to gastric fluid and a good stability of the active principle they contain (omeprazole) within gastric fluid and also when they are stored for a long period of time.
Phillips J. et al. have described a method for preparing omeprazole suspensions using sodium bicarbonate and flavored for children (Phillips J et al.—A prospective study of simplified omeprazole suspension for the prophylaxis of stress-related mucosal damage. Crit. Care Med 1996; 24:1793-800), which is incorporated herein by reference in its entirety).
Before, in 1997 Quercia R. et al., demonstrated that it is possible to extemporaneously prepare a suspension with 2 mg/ml of omeprazole for oral use and which is stable for 14 days at 24° C. from capsules containing omeprazole granules with enteric coating and a solution of sodium bicarbonate (Quercia R. et. al.—Stability of omeprazole in an extemporaneously prepared oral liquid—Vol. 54, Aug. 15, 1997, Am. J. Health—Syst. Pharm.—p. 1833, which is incorporated by reference herein in its entirety).
WO 2005/007117 A2 (2005) describes a powder formulation for suspension containing at least a soluble anti-acid, an inhibitor of the proton pump and a suspension agent preferably xanthan gum, which is incorporated by reference herein in its entirety. This patent remarks the importance of the particle size of the proton pump inhibitor and the presence of the suspension agent in the formulation in order to obtain a good suspendability. It is also noted that the presence of anti-acids in the composition increases the pH level of the gastrointestinal fluid, thus inhibiting the degradation of the proton pump inhibitor in the gastric environment.
EP 0813424 B1 (2002) describes a multi-particulate tablet composition containing an inhibitor of proton pump along with alginate and one or more anti-acid agents, which is incorporated by reference herein in its entirety. The inhibitor of proton pump is under the form of pellets with enteric coating. This fact makes necessary the addition of a prior and specific industrial stage for the elaboration of said pellets.
The above mentioned proceedings and most of those described by the literature mention various conditions needed to assure the stability and efficiency of the inhibitor of proton pump. For example, prior elaboration of enteric pellets, micronization of the inhibitor, addition of suspendibility agents, addition of basic substances to the pellets, etc. All of them require industrial operations and additional equipment (micronizers, fluid bed, dryers, etc.) and generally a much more extended time than the one necessary with the current proceedings for the elaboration of the above described pharmaceutical forms.
The association of the present invention (sodium alginate, soluble anti-acid and inhibitor of proton pump) only uses the routine industrial equipment for the elaboration of pharmaceutical forms destined for oral administration.